Gram-negative bacteria are a major cause of natural outbreaks of disease and feature prominently in the biological arsenals of rogue nations. Compounding this problem is the fact that bacteria are becoming increasingly resistant to current therapeutics, reducing the ability of today's antibiotics to treat the victims of natural outbreaks or attacks from engineered pathogens. We propose to target LpxK, an essential kinase involved in the biosynthetic pathway of Lipid A, a major constituent of the gram-negative outer membrane, as a means to develop novel compounds that can prevent or treat bacterial infections with gram-negative bacteria. Innovative surface-based assays will be used to screen compounds against LpxK. Once promising lead compounds are identified, we will perform iterative rounds of medicinal chemistry, optimizing their ability to block enzymatic modification, their efficacy on a variety of bacteria and their pharmacokinetic properties.